Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Abstract

Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway

“…In addition, interferon gamma response was significantly associated with FABP1 expression in The Cancer Genome Atlas database colorectal tumor data (6). To test if interferon gamma could repress FABP1 expression, two colorectal cancer cell lines were treated with IFNγ.…”

“…Many immmunoregulatory genes activated by IFNγ were upregulated in medullary colorectal carcinomas (6). Of the genes that were differentially expressed or lost in medullary carcinoma, FABP1 was shown to be decreased by 55 fold when compared to normal colon epithelium of the same patient.…”

“…The medullary vs. normal tumor data was previously published (6) and the data are available in Gene Expression Omnibus (GSE76855). We evaluated the signals for the FABP family.…”

“…We evaluated the signals for the FABP family. Normalized HiSeq RNA-seq data for colorectal tumors from The Cancer Genome Atlas were downloaded from Firebrowse in September 2015 (6). Clinical data was downloaded from the The Cancer Genome Atlas data portal (https://tcga.data.nci.gov/tcga/dataAccessMatrix.htm, download in September 2015).…”

“…We initially aimed to examine genes differentially expressed in a subset of MSI tumors (medullary carcinomas) and found expression of the fatty acid binding protein 1 gene ( FABP1 ) to be significantly decreased as compared to adjacent normal mucosa (6). FABP1, also called liver fatty acid binding protein (L-FABP) is an intracellular protein important in the transport of long chain fatty acids.…”